This invention relates to compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof. More particularly, the compounds of the invention are structurally different from NSAIDs and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E.sub.2 (PGE.sub.2) exerts allodynia through the EP.sub.1 receptor subtype and hyperalgesia through EP.sub.2 and EP.sub.3 receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects. These compounds have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
PCT application nos WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996), WO 97/00863 (Jan. 9, 1997), WO 97/00864 (Jan. 9, 1997), WO 96/03380 (Feb. 8, 1996), and EP 752421-A1 (Jan. 8, 1997) disclose compounds represented by Formula I as being useful in the treatment of prostaglandin mediated diseases. ##STR1##
wherein:
A is phenyl, naphthyl, 5- or 6-membered heteroaryl PA1 B is phenyl, 5- or 6-membered heteroaryl or a further defined keto-dihydro ring; PA1 D is phenyl, 5- or 6-membered heteroaryl; PA1 R.sup.1 is COOH, carboxyalkyl, tetrazolyl(alkyl); PA1 R.sup.3 is H or alkyl, and PA1 Z is an alkylene bridge containing 0-1 nitrogen atom or a further defined unsaturated bridge. PA1 Ar.sup.1 is an aryl or heteroaryl group, optionally substituted with R.sup.1 or R.sup.3 ; PA1 R.sup.1 is Y.sub.m --R.sup.2, Y.sub.m --Ar.sup.3, halogen, N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, CON(R.sup.5).sub.2, S(O).sub.n R.sup.7 or OH; PA1 Y represents a linker between R.sup.2 or Ar.sup.3 and Ar.sup.1 containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker optionally containing CO, S(O).sub.n, --C.dbd.C-- or an acetylenic group, and said linker being optionally substituted by R.sup.2 ; PA1 m is 0 or 1; PA1 n is 0,or 2; PA1 R.sup.2 represents H, F, CHF.sub.2, CF.sub.3, lower alkyl or hydroxyC.sub.1-6 alkyl, or two R.sup.2 groups may be joined together and represent a carbocyclic ring of up to six members, said ring containing not more than one heteroatom selected from O, N and S; PA1 Ar.sup.3 represents an aryl or heteroaryl group, optionally substituted with R.sup.3 ; PA1 R.sup.3 is R.sup.4, halogen, haloC.sub.1-6 alkyl, N(Rr).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, CON(R.sup.5).sub.2, OR.sup.4, SR.sup.4 or S(O).sub.n R.sup.7 ; PA1 R.sup.4 is H, lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3 ; PA1 R.sup.5 is R.sup.4, Ph or Bn, or two R.sup.5 groups in combination with the atom to which they are attached represent a ring of up to 6 members containing carbon atoms and up to 2 heteroatoms selected from O, N and S; PA1 R.sup.6 is H, F, CF.sub.3 or lower alkyl, or two R.sup.6 groups may be taken together and represent a ring of up to 6 members containing carbon atoms and 0-2 heteroatoms selected from O, N and S; PA1 R.sup.7 is lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2, CF.sub.3, N(R.sup.5).sub.2, Ph(R.sup.8).sub.2 or CH.sub.2 Ph(R.sup.8).sub.2 ; PA1 R.sup.8 is R.sup.4, OR.sup.4, SR.sup.4 or halogen PA1 W represents a 3-6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, said linking group optionally containing CO, S(O).sub.n, C.dbd.C or an acetylenic group, and optionally being substituted with R.sup.9 ; PA1 R.sup.9 is R.sup.2, lower alkenyl, lower alkynyl, OR.sup.4 or SR.sup.4 ; PA1 Ar.sup.2 represents an aryl or heteroaryl group, optionally ubstituted with R.sup.3 ; PA1 R.sup.10 represents R.sup.4, halogen, N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, OR.sup.4, SR.sup.4 or S(O).sub.n R.sup.7 ; PA1 X represents a linker which is attached to Ar.sup.2 ortho to the attachment of W, said linker containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker further optionally containing CO, S(O).sub.n, C.dbd.C or an acetylenic group, and said linker being optionally substituted with R.sup.11 ; PA1 R.sup.11 is R.sup.9 ; PA1 Q represents a member selected from the group consisting of: CO.sub.2 H, tetrazole, SO.sub.3 H, hydroxamic acid, CONHSO.sub.2 R.sup.12 and SO.sub.2 NHCOR.sup.12 ; PA1 R.sup.12 represents a member selected from the group consisting of: CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl and ZAr.sup.4, wherein Z is an optional linker containing 0-4 carbon atoms, optionally substituted with R.sup.13 ; PA1 R.sup.13 is R.sup.9 ; PA1 Ar.sup.4 is an aryl or heteroaryl group optionally substituted with R.sup.14, and PA1 R.sup.14 is R.sup.10 or NHCOMe. PA1 Ar.sup.1 is an aryl or heteroaryl group, optionally substituted with R.sup.1 or R.sup.3 ; PA1 R.sup.1 is Y.sub.m --R.sup.2, Y.sub.m --Ar.sup.3, halogen, N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, CON(R.sup.5).sub.2, S(O).sub.n R.sup.7 or OH; PA1 Y represents a linker between R.sup.2 or Ar.sup.3 and Ar.sup.1 containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker optionally containing CO, S(O).sub.n, --C.dbd.C-- or an acetylenic group, and said linker being optionally substituted by R.sup.2 ; PA1 m is 0 or 1; PA1 n is 0, 1 or 2; PA1 R.sup.2 represents H, F, CHF.sub.2, CF.sub.3, lower alkyl or hydroxyC.sub.1-6 alkyl, or two R.sup.2 groups may be joined together and represent a carbocyclic ring of up to six members, said ring containing not more than one heteroatom selected from O, N and S; PA1 Ar.sup.3 represents an aryl or heteroaryl group, optionally substituted with R.sup.3 ; PA1 R.sup.3 is R.sup.4, halogen, haloC.sub.1-6 alkyl, N(R.sup.5).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, CON(R.sup.5).sub.2, OR.sup.4, SR.sup.4 or S(O).sub.n R.sup.7 ; PA1 R.sup.4 is H, lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3 ; PA1 R.sup.5 is R.sup.4, Ph or Bn, or two R.sup.5 groups in combination with the atom to which they are attached represent a ring of up to 6 members containing carbon atoms and up to 2 heteroatoms selected from O, N and S; PA1 R.sup.6 is H, F, CF.sub.3 or lower alkyl, or two R.sup.6 groups may be taken together and represent a ring of up to 6 members containing carbon atoms and 0-2 heteroatoms selected from O, N and S; PA1 R.sup.7 is lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2, CF.sub.3, N(R.sup.5).sub.2, Ph(R.sup.8).sub.2 or CH.sub.2 Ph(R.sup.8).sub.2 ; PA1 R.sup.8 is R.sup.4, OR.sup.4, SR.sup.4 or halogen PA1 W represents a 3-6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, said linking group optionally containing CO, S(O).sub.n, C.dbd.C or an acetylenic group, and optionally being substituted with R.sup.9 ; PA1 R.sup.9 is R.sup.2, lower alkenyl, lower alkynyl, OR.sup.4 or SR.sup.4 ; PA1 Ar.sup.2 represents an aryl or heteroaryl group, optionally substituted with R.sup.3 ; PA1 R.sup.10 represents R.sup.4, halogen, N(R.sup.s).sub.2, CN, NO.sub.2, C(R.sup.6).sub.3, OR.sup.4, SR.sup.4 or S(O).sub.n R.sup.7 ; PA1 X represents a linker which is attached to Ar.sup.2 ortho to the attachment of W, said linker containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker further optionally containing CO, S(O).sub.n, C.dbd.C or an acetylenic group, and said linker being optionally substituted with R.sup.11 ; PA1 R.sup.11 is R.sup.9 ; PA1 Q represents a member selected from the group consisting of: CO.sub.2 H, tetrazole, SO.sub.3 H, hydroxamic acid, CONHSO.sub.2 R.sup.12 and SO.sub.2 NHCOR.sup.12 ; PA1 R.sup.12 represents a member selected from the group consisting of: CF.sub.3, lower alkyl, lower alkenyl, lower alkynyl and ZAr.sup.4, wherein Z is an optional linker containing 0-4 carbon atoms, optionally substituted with R.sup.13 ; PA1 R.sup.13 is R.sup.9 ; PA1 Ar.sup.4 is an aryl or heteroaryl group optionally substituted with R.sup.14, and PA1 R.sup.14 is R.sup.10 or NHCOMe. PA1 Ar.sup.1 is an aryl or heteroaryl group substituted by R.sup.1 and R.sup.3 ; PA1 R.sup.1 is OH, OCH.sub.2 Ar.sup.3, SCH.sub.2 Ar.sup.3, OAr.sup.3, SAr.sup.3 or NR.sup.2 CH.sub.2 Ar.sup.3 ; PA1 Ar.sup.3 is selected from the group consisting of benzene, pyridine, thiophene, furan, oxazole and thiazole, said group being optionally substituted with R.sup.3 ; PA1 Ar.sup.2 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole, and thiazole, said group being optionally substituted with 1-4 members selected from the group consisting of: R.sup.4, OR.sup.4, SR.sup.4 and halogen; PA1 W is selected from the group consisting of: CH.sub.2 OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2 CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH, CH.dbd.CHCH(OH), CH.sub.2 C.tbd.C , C.tbd.CCH.sub.2 1,2-c-Pr--CH.sub.2 -- and --CH.sub.2 -1,2-c-Pr-; PA1 X is selected from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH, C.tbd.C and 1,2-c-Pr; PA1 and Q is CO.sub.2 H or tetrazole. Within this subset, all other variables are as originally defined. PA1 Ar.sup.1 is an aryl or heteroaryl group optionally substituted with R.sup.1 and R.sup.3 ; PA1 R.sup.1 is OH, OCH.sup.2 Ar.sup.3, SCH.sub.2 Ar.sup.3, OAr.sup.3, SAr.sup.3 or NR.sub.2 CH.sub.2 Ar.sup.3 ; PA1 Ar.sup.3 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole or thiazole, said group being optionally substituted with R.sup.3 ; PA1 W is selected from the group consisting of: CH.sub.2 OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2 CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH, CH.dbd.CHCH(OH), CH.sub.2 C+C or C.tbd.CCH.sub.2 ; PA1 Ar.sup.2 represents a member selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole or thiazole, said group being optionally substituted with R.sup.8 ; PA1 X is is selected from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH, C.tbd.C and 1,2-c-Pr; PA1 Q is CONHSO.sub.2 ZAr.sup.4 ; PA1 Z is a 0-2 carbon linker and is unsubstituted; PA1 Ar.sup.4 is selected from the group consisting of: benzene, pyridine, thiophene, furan, oxazole, thiazole, 1,3,4-thiadiazole and naphthalene, and is optionally substituted by R.sup.3. Within this subset, all other variables are as originally defined. PA1 A more preferred aspect of the invention relates to compounds represented by formula II wherein: PA1 Ar.sup.1 is benzene or thiophene substituted in position 2 and/or position 4 relative to the attachment of W with a member selected from the group consisting of: OH, OCH.sub.2 Ar.sup.3, SCH.sub.2 Ar.sup.3, OAr.sup.3, SAr.sup.3 and NR.sup.2 CH.sub.2 Ar.sup.3, and is optionally substituted in position 3 with a member selected from the group consisting of: OMe, OCHF.sub.2 and lower alkyl; PA1 Ar.sup.3 is benzene or thiophene, optionally substituted with R.sup.8 ; PA1 W is selected from the group consisting of: CH.sub.2 OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2 CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH and CH.dbd.CHCH(OH), PA1 Ar.sup.2 is benzene or thiophene, optionally substituted with 1-4 members selected from R.sup.4, OR.sup.4, SR.sup.4 and halogen; PA1 X represents a member selected from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH and 1,2-c-Pr, and PA1 Q is CO.sub.2 H. PA1 Ar.sup.1 is a benzene or a thiophene unsubstituted or substituted in position 2 and/or position 4 relative to the point of attachment to W by a member selected from the group consisting of: OH, OCH.sub.2 Ar.sup.3, SCH.sub.2 Ar.sup.3, OAr.sup.3, SAr.sup.3 and NR.sup.2 CH.sub.2 Ar.sup.3 ; and is optionally substituted at position 3 with one member selected from the group consisting of: OMe, OCHF.sub.2 and lower alkyl; PA1 Ar.sup.3 is benzene or thiophene, optionally substituted with R.sup.8 ; PA1 W is selected from the group consisting of: CH.sub.2 OCH.sub.2, (CH.sub.2).sub.3, CH.sub.2 CH.dbd.CH, CH.dbd.CHCH.sub.2, CH(OH)CH.dbd.CH and CH.dbd.CHCH(OH); PA1 Ar.sup.2 is benzene or thiophene, optionally substituted with R.sup.4, OR.sup.4, SR.sup.4 or halo; PA1 X is selected from the group consisting of: (CH.sub.2).sub.2, CH.dbd.CH and 1,2-c-Pr, PA1 Q is CONHSO.sub.2 ZAr.sup.4, PA1 Z is a bond or CH.sup.2, and PA1 Ar.sup.4 is selected from the group consisting of: benzene, thiophene, 1,3,4-thiadiazole and naphthalene and is substituted with R.sup.8. PA1 Ar.sup.1 represents phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl; PA1 R.sup.1 represents H, OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyC.sub.1-6 alkyl, aryl, aryloxy, arylalkoxy, haloaryl, haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy, haloarylalkoxy and haloheteroarylalkoxy; PA1 R.sup.3 represents R.sup.4, halogen, OR.sup.4 or SR.sup.4 ; PA1 R.sup.4 represents H, lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3 ; PA1 X represents a member selected from the group consisting of: --(CH.sub.2).sub.1-2 --, 1,2-c-Pr, --CH.dbd.CH--, --CH.sub.2 O--, --C.dbd.CCH.sub.2 --, --C.tbd.C--, and --CH.sub.2 --C.tbd.C--; PA1 W represents a member selected from the group consisting of: PA1 Ar.sup.1 represents phenyl, naphthyl, benzofuranyl or methylenedioxyphenyl; PA1 R.sup.1 represents H, OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyC.sub.1-6 alkyl, aryl, aryloxy, arylalkoxy, haloaryl, haloheteroaryl, haloarylalkoxy, alkylaryl, haloalkylarylalkoxy, haloarylalkoxy and haloheteroarylalkoxy; PA1 R.sup.3 represents R.sup.4, halogen, OR.sup.4 or SR.sup.4 ; PA1 R.sup.4 represents H, lower alkyl, lower alkenyl, lower alkynyl, CHF.sub.2 or CF.sub.3 ; PA1 X represents a member selected from the group consisting of: PA1 W represents a member selected from the group consisting of: PA1 R.sup.12 is selected from the group consisting of: C.sub.1-6 alkyl, thienyl, phenyl, naphthyl, biphenyl, quinolinyl, thiadiazolyl, tetrazolyl, --CH.dbd.CH-phenyl, said thienyl, phenyl, naphthyl, biphenyl, quinolinyl, thiadiazolyl, tetrazolyl and --CH.dbd.CH-phenyl groups being optionally substituted with R.sup.3. PA1 pain, fever, inflammation, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine, toothache, sprains, strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout, ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases, cellular neoplastic transformations, metastatic tumor growth, prostaglandin-mediated proliferation disorders such as diabetic retinopathy and tumor angiogenesis, dysmenorrhea, premature labor, asthma, eosinophil related disorders, Alzheimer's disease, glaucoma, bone loss (osteoporosis), promotion of bone formation (treatment of fractures) and other bone diseases such as Paget's disease.
Compound Ia is one of the compounds specifically claimed.